tbuckley/cabot-search huggingface dataset:
Effect of neoadjuvant therapy pathway (NATP) for pancreatic cancer on overall patient outcomes.
Authors: Dylan Cooper, Baho Sidiqi, Ruwan Parakrama, Lyudmyla Demyan, Shamsher Pasha, Danielle Pinto, Tiffany Zavadsky, Xianghui Zou, Sunita Patruni, Adrianna Kapusta, Oliver Standring, Jason Nosrati, Leila T Tchelebi, Matthew John Weiss, Joseph M. Herman, Daniel King
Journal: Journal of Clinical Oncology (2023)

695 Background: Significant variation exists in the management of potentially resectable pancreatic ductal adenocarcinoma (PDAC) across healthcare systems. We describe the results of a newly implemented neoadjuvant therapy pathway (NATP) in New York’s largest, most diverse health care system. Methods: The NATP was established in June 2019, consisting of a single-day pancreas multi-disciplinary clinic (PMDC) visit, followed by neoadjuvant therapy (NAT), imaging at specific intervals, and PMDC re-reviews at two and four months, prior to consideration of radiation and surgical resection. We conducted an IRB-approved retrospective analysis of patients enrolled in this pathway. Primary endpoints included completion of NATP and overall survival (OS). Results: The cohort consisted of 67 patients reviewed at PMDC and planned for NAT: 45% men, mean age 69.9 years, and 43% non-White between June 2019 and February 2022. Surgical stage at diagnosis was locally advanced (LAPC) 48%, borderline resectable (BRPC) 37% and resectable (RPC) 15%. Of 67 patients, 55 began the NATP (9 transferred care, and 3 declined NAT) and 28 (51%) completed NATP and underwent surgical exploration. Ten completed NATP and did not become surgical candidates, and 2 are still undergoing NAT. NATP was not completed in 15 patients due to 11 metastases (73.3%), 3 deaths (20%) and 1 local progression (6.7%) during NAT. NAT consisted of gemcitabine/nab-paclitaxel (GnP, 28%; 201 total cycles), FOLFIRINOX (45%; 251 total cycles), or a combination of both regimens (26%) with 31 (56%) patients receiving radiotherapy (97% SBRT). Of 28 patients who were explored, 86% underwent successful resection (62.5% R0, 16.7% R1 &lt; 1mm and 20.8% R1). With median follow-up of 12.6 months, there were 17 deaths (31%) and median OS was reached at 20.9 mo (95% CI 10.5, 31.2); GnP vs. FOLFIRINOX median OS were 12.7 mo (95% CI 7.8, 17.6) vs. 26.1 mo (95% CI 9.3, 42.9) (p = 0.026). Median OS was not reached for the resected patients vs.16.3 months for non-resected (p = 0.006). Pathway adherence was seen in 28 (53%), with adherence improving median OS 20.9 mo vs. 16.3 mo (p = 0.039). NATP completion improved median OS 26.1 mo vs. 15.9 mo (p &lt; 0.001). The percentage of patients that remained within the Northwell Health system for their post-NAT was higher among patients in the pathway, compared to prior (87% versus 44%). Conclusions: Implementation of NATP for pancreatic cancer within a single healthcare system increased the percentage of PDAC patients who underwent surgical resection and improved patient retention rate. Our data lay the foundation for further analysis of long-term outcomes of NAT in these patients.
What genes predict response to neoadjuvant chemoradiation in locally advanced rectal cancer? A systematic review based on gene expression profiling.
Authors: Michelle Or, Jessica Lin, Johnson Lam, Eric Hau, Puma Sundaresan
Journal: Journal of Clinical Oncology (2023)

200 Background: Curative management of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiation therapy (nCRT) followed by radical surgery. Pathological complete response (pCR) is seen in 15-27% of patients. The response to nCRT may be influenced by genetic variations. Gene signatures therefore may serve as biomarkers for predicting response or resistance to nCRT. We conducted a systematic review on genetic biomarkers for response prediction to nCRT in LARC and identify common genes or ontology pathways. Methods: A systematic search of electronic databases (MEDLINE, PubMed and EMBASE) was performed for relevant recent studies. Studies were screened as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with search terms “rectal neoplasm”, “rectal cancer”, “gene”, “gene expression”, “gene expression profile”. The relevant studies were selected for full-text review. Studies that reported gene expression profile to predict response to nCRT were included. Results: Twelve of 367 studies screened were included. Most studies used microarray or real-time reverse transcription PCR. Six of these assessed for gene predictors of pCR with 2 studies reporting correlation between certain genes and pCR: thymidylate synthetase; gene set (including LMNB2, MLF2, DDX1, EIF4A1, FOXO3A, ILF3 and SEMA3C); 19 genes including (NPSR1, HYAL1, FGFBP1, PLLP and MALL). Common gene ontology pathways identified included DNA break repair via homologous recombination and apoptotic pathways. Conclusions: Multiple genes were identified as prospective biomarkers for nCRT in LARC patients. Further studies are required to validate these identified genes to personalize treatment for LARC patients.
The genomic landscape of advanced gastrointestinal (GI) neuroendocrine tumors (NET) and carcinomas (NEC).
Authors: Nicole Farha, Prabhjot Singh Mundi, Wei Wei, Suneel Deepak Kamath, Alok A. Khorana, Antonio Tito Fojo, Bahar Laderian
Journal: Journal of Clinical Oncology (2023)

656 Background: The impact of specific genomic alterations in advanced GI neuroendocrine malignancies on prognosis and treatment decisions has not been fully characterized. In this study, we seek to evaluate next-generation sequencing (NGS) panels and corresponding clinical outcomes in patients with metastatic GI NET/NEC. Methods: Patients with GI-NET/NEC were identified from a database of NGS reports performed at the Cleveland Clinic, and clinical variables were extracted by chart review through an IRB-approved protocol. We provide an analysis of this cohort. Results: Of a total n=45 patients, 53% were male. Median age at diagnosis was 60 (range: 35-90 years) and 82% were non-Hispanic white, while 9% were black. There were n=25 GI-NETs, mostly intermediate or high grade (11 G3, 7 G2), and n=20 GI-NECs. There was a balanced distribution of primary sites, including colorectal (27%), pancreas (24%), small intestine (18%), unknown primary (24%) and a single case of biliary primary. High grade GI-NETs and GI-NECs were over-represented in the colorectal primary group vs other sites. (n=10 of 12; p=0.021). The majority of patients (73%) had at least one somatic variant, including 12 patients (27%) with one or more mutations deemed actionable, but only one patient (with MSH2 mutation) has received a mutation-matched drug (pembrolizumab). Some recurrent alterations appeared to co-segregate with aggressive histology (NEC vs NET), including 12 of 13 TP53 mutations (p&lt;0.05 by Fisher Exact Test), 7 of 8 RB1 (p&lt;0.05), and 5 of 6 APC (p=0.074). The most common mutations per person based on primary site is shown. Microsatellite instability high was rare (n=1) and median tumor mutational burden (TMB) was 3/mb, with TMB lower in NETs vs NECs. A number of patients (35%) underwent germline testing, with 6 of 16 having a pathogenic germline variant. Conclusions: As 42% of the 12 patients with actionable mutations were alive at time of analysis, it is possible that additional patients could be treated with mutation-matched therapies. More input will be needed from providers as to the role played by alternative effective treatments and barriers such as insurance coverage and prior authorization to implementing mutation-matched therapies. Given the overall low TMB of GI-NETs, with several tumors having zero or 1 reported mutation on targeted NGS, whole genome sequencing may prove useful. Finally, certain mutations such as RB1 and TP53 were associated with more aggressive histology (i.e. NEC). Lastly, only 9% of our cohort with NGS were black, a significant under-representation based on epidemiological data, which raises concerns about disparate accessibility and barriers to NGS testing. Further studies are needed to address any possible racial disparity.[Table: see text]
Rates of unplanned hospital care in Black Americans with pancreatic cancer.
Authors: Kristen M John, Harkirat S Dhillon, Daniel King
Journal: Journal of Clinical Oncology (2023)

666 Background: Individuals with cancer are more likely to visit an emergency department (ED) for issues both related and unrelated to their cancer than individuals without cancer, but data are lacking regarding what subpopulations are most vulnerable. Here, we assessed the characteristics of patients with pancreas cancer across the Northwell Health system who had multiple ED visits. Methods: An IRB-approved retrospective chart review of patients with pancreas cancer diagnosed between 2015 through 2021 was conducted. Patients with &gt; 3 ED visits were defined as high utilization and patients with 0 ED visits were defined as low utilization. Demographic and clinical features were recorded. Median income was extrapolated by zip code using data from the US Census Bureau. Generalized logistic regression models were constructed to analyze characteristics associated with high ED utilization. Results: The cohort consisted of 658 patients, among whom 181 individuals met criteria for high utilization and 140 met criteria for low utilization. Stage, age, gender, ethnicity, history of pancreatitis, median income, preferred language, establishment with primary care provider, and establishment with medical oncologist had no significant association with high utilization. Race (OR: 2.8; p = 0.002) and substance abuse (OR: 4.43; p = 0.02) were the strongest predictors of high ED utilization. We observed that 14% of the individuals who were Black had a history of substance abuse. Conclusions: Our analysis identified a striking and concerning association between high utilization of the ED and patients who are Black or who have a history of substance abuse. Substance abuse may contribute to high ED utilization among Black Americans, however, 86% had no history of substance abuse, suggesting that other causal factors are at play. These results compel further investigation into these casual factors to guide the development of health equity interventions to address these disparities.[Table: see text]
Multidimensional characterization of early-stage gastric cancer: Preliminary results of MIMETIC trial.
Authors: Silvia Catanese, Carlotta Catozzi, Angeli Dominique Macandog, Nicola Fazio, Uberto Fumagalli, Giuseppe De Roberto, Stefano De Pascale, Luigi Funicelli, Annarita Sabbatini, Patrizia Gnagnarella, Luigi Nezi, Lorenzo Gervaso, Chiara Alessandra Cella
Journal: Journal of Clinical Oncology (2023)

422 Background: Gastric adenocarcinoma (GA) represents a leading cause of cancer death worldwide. For localized and locally advanced (LA) GA, accounting for 30% of new diagnoses, surgery, with or without peri-operative chemotherapy (CTX), remains the cornerstone of treatment. Nevertheless, the cure rate remains unsatisfactory. Genomic biomarkers have been tested to tailor anticancer treatments, but no one is able to guide the treatment choice in GA. Gut microbiota represents an emerging area of investigation in cancer, as a key modulator of host immune response. However, its role in GA on treatment tolerability and outcome is not unraveled. Additionally, radiomics, which can perform massive data mining to increase diagnostic power, and extensive dietary assessment are fast-growing tools. Our aim is to set an innovative approach to mapping the interaction among nutrition, microbiome, genomics, and radiomics and correlate them with clinical outcomes. Methods: We are conducting a prospective observational trial in GA patients (pts), candidates to receive peri-operative CTX or upfront surgery. For each patient, we longitudinally collect blood, fecal and salivary samples, alongside clinical and nutritional information. Additionally, past dietary consumption is measured using the food frequency questionnaire. At baseline, CT scan for staging, radiomic analysis, upper digestive endoscopy with biopsy, and molecular biomarkers are performed. Additional samples are taken from tumor and surrounding normal mucosa (1 to 3 cm) for microbiome analysis. Genomic DNA from stool, buccal and gastric tissue samples will be extracted and subjected to 16S metagenomic sequencing. Taxonomic and functional features within and between anatomical compartments will be correlated with clinical and radiomic data. Results: Here, we are presenting preliminary data of fecal samples from 35 GA pts in comparison with a cohort of healthy subjects (HCs) collected at our Institution. Pts’ characteristics are outlined here. We observed that the structure of the gut microbiota of GA pts is distinct from HCs in terms of beta diversity, and this difference is maintained after CTX. In particular, GA’s microbiota was enriched in S. anginosus, among other taxa. Conclusions: Our preliminary data support the feasibility of the study. The differences in structure and composition of the gut microbiota of GA pts compared to HCs confirm previous reports while providing the rationale for developing gut microbiota profiling into a non-invasive biomarker, to implement early diagnosis and prevention. The study is ongoing and actively recruiting.[Table: see text]
Real-world treatments and outcomes of resected biliary tract cancers in British Columbia, Canada.
Authors: Mélina Boutin, Maria Safro, Jenny Yang, Helia Jafari, Janine Marie Davies, Sharlene Gill
Journal: Journal of Clinical Oncology (2023)

505 Background: Complete resection followed by adjuvant chemotherapy is standard of care for patients with localized cholangiocarcinoma (CC) or gallbladder cancer (GBC) but is not always feasible and recurrence rates remain high. Understanding the exact proportions and reasons for treatment failure is important to design new approaches, data regarding this information remain scarce. Methods: We performed a retrospective population-based review of patients with GBC or CC (intrahepatic (ICC) or extrahepatic (ECC)) resected between 2005-2019 using the BC Cancer provincial database. Chart review was conducted to characterize demographics, treatments and outcomes. Results: 594 patients were identified of whom 416 (70%) had disease recurrence. Baseline characteristics and treatments received are shown in the table. Most GBCs (96%) were diagnosed incidentally. Repeat oncologic resection was performed for 55% of these, the most common reason for not proceeding was interval disease progression between initial cholecystectomy and planned re-resection (24%). Adjuvant chemotherapy was received by 51% of 163 patients after 2017 and consisted of capecitabine (86%), gemcitabine (4%), cisplatin and gemcitabine (5%) or chemoradiation (4%). Common reasons for not receiving adjuvant therapy were post op complications or comorbidities (18 and 24%), progression (17%) and patient’s preference (17%). Of those receiving adjuvant therapy, 31% did not complete all planned cycles due to progression (45%) or intolerance (55%). Median overall survival (OS) after resection was 31.6 and 18.0 months respectively for R0 and R1 resection (HR 0.43, 95% CI 0.35-0.53), 29.4 and 19.0 months with and without reresection for GBC (HR 0.55, 95% CI 0.41-0.73), and 29.4 and 25.9 months with and without adjuvant therapy (HR 0.79, 95% CI 0.61-1.02). Stage, R0 resection, re-resection for GBC and adjuvant chemotherapy remained associated with improved OS in multivariate analysis. Taken together, only 25% of patients in the more contemporary cohort of 2017-2019 had complete (R0) resection and completed adjuvant chemotherapy. Conclusions: Complete resection, including reresection for incidentally diagnosed GBCs, and adjuvant chemotherapy were associated with improved outcomes in this retrospective cohort, yet many patients were not able to complete these treatments. Neoadjuvant strategies may improve treatment delivery and ultimately, outcomes. [Table: see text]
An adaptive approach to neoadjuvant therapy to maximize resection rates for pancreatic adenocarcinoma: A phase II trial.
Authors: Davendra Sohal, Jordan Kharofa, Olugbenga Olanrele Olowokure, Adam Rojan, Sameer H. Patel, Gregory C. Wilson, Jeffrey J. Sussman, Katie Moreland, Krushna Patra, Vladimir Bogdanov, Taylor S Riall, Yana Zavros, Rachna T. Shroff, Syed A. Ahmad
Journal: Journal of Clinical Oncology (2023)

TPS771 Background: Curative treatment for potentially resectable (resectable or borderline resectable) pancreatic adenocarcinoma, despite recent advances, leads to only suboptimal outcomes. Recent US national cooperative group trials have demonstrated the safety and feasibility of neoadjuvant chemotherapy (PMID 33475684, PMID 35834226), and also show that the two frontline regimens, FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine/nab-paclitaxel (GnP), are comparable in this setting. Finally, ability to undergo resection remains the key driver of cure. Therefore, an approach that selects chemotherapy based on early response assessment, to maximize the probability of resection, is likely to improve curative outcomes. Methods: This is a phase II study intended to maximize the probability of surgical resection for pancreatic cancer. Key eligibility requirements include adult patients with a confirmed histopathologic diagnosis of pancreatic carcinoma or adenocarcinoma, an ECOG PS ≤ 1, resectable or borderline resectable disease by central radiology review, no prior therapy for index pancreatic cancer, and adequate bone marrow, liver and kidney function. Treatment includes 4 doses (~ 2 months total treatment time) of FOLFIRINOX (“Chemo1”). After a re-evaluation, using radiologic response, CA19.9 response, and chemotherapy toxicity, patients will either continue with “Chemo1” for another 4 cycles (8 doses) or switch to GnP (“Chemo2”) which will be administered for 4 cycles (12 doses, for ~4 month total treatment time), followed by surgical resection. Primary outcome will measure the proportion of patients undergoing surgical resection using historical dated compared to 32 patients in a current study with a time frame of 16 months. Using historical data, the expected proportion of patients undergoing resection is ~60%. The goal of this study is to increase this to 80% or higher. With a one-sided of 0.05 and power of 80%, 32 patients will be needed to demonstrate this difference. Key translational correlatives will include serial circulating tumor DNA assessment and extensive tumor molecular profiling. Clinical trial information: NCT04594772 .
Effect of immunotherapy on the survival outcomes in tumor mutational burden-high (TMB-H) microsatellite stable (MSS) metastatic colorectal cancer (mCRC): A single-institution experience.
Authors: Ola Gaber, Canan Karan, Christine Marie Walko, Todd C Knepper, Richard D. Kim, Ibrahim Halil Sahin
Journal: Journal of Clinical Oncology (2023)

239 Background: The benefit of immunotherapy for patients with mCRC with high tumor mutational burden (TMB-H) has been widely debated. In 2020, the FDA approved the use of pembrolizumab for the treatment of patients with TMB-H unresectable or metastatic solid tumors, with TMB-H defined as ≥10 mutations/Mb on a commercial tissue-based assay, based on KEYNOTE 158 results. However, the clinical value of applying this universal cut off to mCRC needs further investigation. Methods: We queried Moffitt Cancer Center (MCC) databases for patients with MSS mCRC, harboring TMB-H (tested with tissue and/or liquid biopsies) who received immunotherapy between January 2018 and December 2021. Patients with incomplete records were excluded. Clinical data were extracted by trained staff from electronic medical records. Objective response rate was measured by using clinical assessment from chart review. Results: We identified 40 patients with TMB-H MSS mCRC 13 of whom received immune checkpoint inhibitor therapy. Female patients represented 31% (n=4) of the 13 treated patients. Median age for the patients was 60 years (range 34-71. Thirty-eight percent (n=5) of the primary tumors originated in the right side. Thirty-one percent (n=4) presented with stage 4 CRC at diagnosis. Histopathology was adenocarcinoma in 92% (n=12) and one had neuroendocrine differentiation. Tumors were well-differentiated 8% (n=1), moderately differentiated 46% (n=6), or poorly differentiated 23% (n=3). Four patients (31%) had POLE/ POLD-1 mutations. The objective response rate (ORR) was 31% (4/13) with responses limited to tumors only with POLE/ POLD-1 mutations (100%, 4/4). The median progression free survival (mPFS) was 3.8 months for the overall cohort and 28.5 months for patients with POLE/POLD-1 mutated tumors. Agent specific analysis showed mPFS for patients treated with pembrolizumab was 3.5 months (mean 5.2; range 0.6-15.7), and 3.4 months (mean 12.1; range 0.5-12.1) for patients treated with nivolumab. Five patients received immunotherapy in combination with regorafenib. The mPFS for these patients was 3.4 months (mean 3.8; range 0.5-8.0). Of five patients with TMB&gt;30 (38%), 4 (80%) had POLE/POLD-1 mutated tumors. One case without POLE/POLD-1 mutations, but with a TMB&gt;30 did not experience any response. Conclusions: Although TMB-H demonstrated therapeutic significance in the KEYNOTE 158 study, the utility of 10 mutations/MB as a universal cutoff warrants additional evaluation. Here we report that a TMB-H cutoff value of ≥ 10 for patients with MSS CRC was not associated with clinically meaningful response to immunotherapy, but patients with MSS CRC with POLE/ POLD-1 mutations may be more likely to benefit from immunotherapy.
Phase Ib study of dabrafenib, trametinib, irinotecan and cetuximab in BRAF V600E-mutated metastatic colorectal cancer.
Authors: Yungchang Chen, Xiaoqian Li, Man Yuxin, Hai Hu, Liyang Wang, Zhixuan Zhang, Ping Chen, Yang Liu, Jin Lu, Tongyu Lin
Journal: Journal of Clinical Oncology (2023)

156 Background: The low efficacy of single-agent BRAF inhibitor in metastatic colorectal cancer (mCRC) is usually due to EGFR feedback upregulation caused by BRAF blockade. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. Here, we reported the preliminary results of quadruple therapy with dabrafenib, a selective BRAF inhibitor, trametinib, a selective MEK inhibitor, irinotecan and cetuximab in patients with BRAF V600E-mutated mCRC. Methods: This was an ongoing phase Ib study, patients with mCRC who relapse or refractory to standard treatments were enrolled. Patients were treated with dabrafenib (150mg/150mg doses orally twice daily), trametinib (2mg orally once daily), irinotecan (80mg/m 2 weekly) and cetuximab (400mg/m 2 in first dose and 250mg/m 2 weekly). Treatment was continued until disease progression, development of unacceptable toxicity, or drawal of consent. The primary end-point was disease control rate (DCR), and the secondary end-points included progression-free survival (PFS) and duration of disease remission (DOR). This trial is registered with Chinese ClinicalTrials.gov, number ChiCTR2200063316. Results: From July 2018 to January 2021, 10 patients were enrolled. The median age was 53.5 (age 25-65), nine with colon cancer and one with rectal cancer. The most common adverse events (AEs) (50% or more) were fatigue, fever, rash, vomit, leukopenia, anemia, ALT elevation, and AST elevation. Four patients suffered rash which was the most common severe AE (SAE). Two patients presented with grade 3/4 anemia. Only one patient suffered grade 3/4 AEs with nausea and vomit. The DCR was 90% (9/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months (range 1.8-32.4 months). The median DOR was 5.2 months (range 0-27.7 months). Conclusions: Dabrafenib, trametinib, irinotecan and cetuximab has tolerable toxicity and promising antitumor activity in BRAF V600E-mutated mCRC. This regimen warrants a further phase II clinical trial. Clinical trial information: ChiCTR2200063316 . [Table: see text]